Medical School 2020, Year 2, Week 12

From our anonymous insider…

Hematology week. Our favorite redheaded hematologist/oncologist: “Heme is a free-for-all. Oncology is more by-the-book. Our whole practice has no idea what is causing one patient’s hematological abnormalities. We’ve been following him for 3 years. This is what makes hematology so exciting.”

Blood is composed of cells and plasma (water, electrolytes, and proteins). As introduced in the Year 1, Week 7 and Year 1, Week 16 chapters, all blood cells are derived from a single hematopoietic bone marrow stem cell that can produce either the myeloid lineage or the lymphoid lineage. The myeloid lineage includes erythrocytes (red blood cells), platelets (for clotting), monocytes (white blood cells that consume particles), and neutrophils (the most abundant immune cell that responds to infections). The lymphoid lineage includes the immune system’s T cells and B cells.

Platelets start as small cytoplasmic blebs (bulge in the cell) of megakaryocytes (large resident bone marrow cells) and eventually detach and drift away. Erythrocytes (red blood cells) mature in the bone marrow until they lose their nucleus. “If you see reticulocytes [immature red blood cells] in the blood, the bone marrow is working in overdrive producing red blood cells.”

Our lecturer explained the complete blood count (CBC), the most common blood test. Normal CBC: 45 percent of blood volume is composed of red blood cells (hematocrit), 55 percent plasma (proteins, electrolytes, water), and less than 1 percent white blood cells and platelets. “Do not forget about the peripheral blood smear [looking at a drop of blood through a microscope]. It’s vastly underutilized. You can catch iron deficiency before counts get low.” The hematologist emphasized contextualizing a CBC: “Before you jump to pathological anemia, is this patient over-hydrated? If they are hooked up to IV saline, they are going to have lower counts even though the total rbc mass may be normal.”

Anemia is divided into problems of underproduction or destruction. “Destruction anemias are caused by an intrinsic or extrinsic factor. Intrinsic anemia is caused by a defect in the red blood cell itself, such as the membranopathy hereditary spherocytosis or the oxidative damage from an enzyme defect such as glucose-6-phosphate dehydrogenase. Extrinsic anemia is due to destruction of the red blood cell from the outside.” This can be due to an autoimmune reaction against red blood cell surface proteins or a platelet disorder causing small thrombi to form in the vasculature shearing normal red blood cells.

“Use the Coombs test to differentiate between intrinsic and extrinsic disorders.” The Coombs test mixes the patient’s blood with an antibody against human antibodies. If the immune system is attacking its own cells, the anti-Ig antibody will cause the red blood cells to precipitate out of solution.

When so many red blood cells are destroyed that the body demands more, immature red blood cells that still have nuclear material (reticulocytes) are released into circulation. “Always ask for the reticulocyte count if you suspect an anemia of destruction.”

The next two lectures detailed hemostasis (clotting) disorders and the body’s two systems for preventing bleeding. Primary hemostasis plugs the damaged blood vessel with platelets. Secondary hemostasis creates a more stable clot by using clotting factors, proteins released by the liver. Primary hemostasis disorders are associated with mucosal bleeding (gums, menorrhagia, epistaxis), whereas secondary disorders such as hemophilia lead to severe internal bleeding, especially in joints (hemarthrosis).

Our patient case: Gina, a 51-year-old secretary presented to her internist after gingival (gum) bleeding from a dental cleaning. She described bruising easily and itchiness after hot showers (aquatic pruritus). A CBC reveals an elevated hematocrit (extra hemoglobin) and a high platelet count. She was surprised to be diagnosed with polycythemia vera (PV): “I did not know I was sick until the doctor told me I was sick.”

PV is a type of myelodysplastic disorder. A mutated myeloid stem cell, most commonly a JAK2 gain-of-function mutation, causes unchecked clonal proliferation of the myeloid lineage. This results in erythrocytosis (increased red blood cells), thrombocytosis (increased platelets), and leukocytosis (increased white blood cells, specifically of the the myeloid lineage).

Gina started with low-dose aspirin and biweekly phlebotomy (blood draws) to decrease her platelet function and hematocrit, respectively. Straight Shooter Sally: “Can she donate the removed blood?” The hematologist responded, “Great question, in many countries yes. In the US, the Red Cross will not accept anyone with an abnormal CBC. It is a shame because there is nothing abnormal about her denucleated red blood cells.”

PV increases the risk of thrombotic events (clots, stroke, heart attack) due to the increased thickness of blood. According to UpToDate, the annual incidence of thrombosis in PV patients ranged from 2-5 percent depending on risk factors such as age and hematocrit management, which compares to annual stroke risk of 5.6 percent for a 75-year-old smoker with hypertension and diabetes.

PV patients have a 20-percent lifetime risk of their PV transforming into myelofibrosis and a 7-percent lifetime risk of acute myeloid leukemia. “PV overworks the bone marrow,” explained the hematologist. “Myelofibrosis is what you get when you wear it out.” Bone marrow becomes fibrotic with collagen (fibrous protein found in bone, tendons, and ligaments) deposition displacing the stem cells. This causes an abrupt aplastic anemia with extramedullary (outside the bone) hematopoiesis. PV turning into leukemia happens because rapid clonal proliferation increases the chance of an oncogenic mutation (cancer-producing mutation).

“When it rains it pours,” recounted Gina. “I had left my husband. I was going through divorce, I had a new boss trying to cut costs at work, and my son was jobless after graduating from college. Now I have my doctor using all these fancy words and telling me I might have cancer. It was too much.” A student asked: “Did you have any issues dealing with health insurance during the divorce.” “No, I was the primary insurer.” The heme/onc added, “I have issues with insurance and divorce all the time. Also, when the patient with insurance is diagnosed with leukemia and has to stop working. The family has trouble switching primary insurance to the other spouse.”

[Editor: note Gina’s description of being involved in a divorce lawsuit that she started as “going through a divorce.” This is conventional for American plaintiffs, as though divorce litigation were a random weather phenomenon that they had stumbled into. See Real World Divorce.]

Could Gina describe the itchiness? “Every time I got out of a hot shower, I would have this uncontrollable itchiness for a few hours. It got so bad I would be afraid to shower!” The hematologist added, “There are a few theories out there to explain this phenomenon. One theory states the increased myeloid white blood cells cause increased histamine release. This doesn’t make sense because patients can get the itchiness even without leukocytosis [high WBC]. The other theory is platelet aggregation after vascular constriction in the skin after a hot shower.”

Gina, now 66, returned to her hematologist about a year ago due to acute left flank pain, fatigue, and poor appetite with a 15 pound weight loss over a two-month period. Physical exam revealed a palpable mass on her left upper flank. CBC showed pancytopenia (low cell counts across the board). A bone marrow sampling revealed diffuse fibrosis.

The hematologist explained that bone marrow sampling has two steps: “First a needle is inserted into the bone. A vacuum is created to suck bone marrow aspirate into the syringe. Then, a small sample of bone is extracted for biopsy. I am told that the aspirate step is the excruciatingly painful part.” Gina interjected, “It feels like a lightening bolt traveling through your bone.” Her bone marrow cells have been expelled from the fibrosed marrow and now reside in her spleen, liver, pleural cavity and peritoneum. The enlarged spleen is compressing her stomach, which makes her easily satiated and explains the weight loss [Editor: when will be able to buy one of these spleens on Amazon?]. She was diagnosed with myelofibrosis and informed that her life expectancy was just seven years.

The only curative therapy for myelofibrosis is an allogeneic (from a different person) stem cell transplant to replace the defective myeloid clonal population. Gina was not a transplant candidate given her age. She was started on Jakafi (ruxolitinib), a small-molecule inhibitor of JAK2. Jakafi may relieve symptoms of myelofibrosis, but does not improve survival [Editor: except for the survival of Incyte Corporation, which collects roughly $1 billion per year from this “ophan drug”].

The hematologist recounted Gina’s Jakafi-induced anemic crisis: “Jakafi is a double-edged sword. It can improve symptoms, but it also risks causing an anemic crisis. We followed the drug’s guidelines but Jakafi was such a new drug. We took her off the drug, but then she had withdrawal requiring two transfusions. We titrated her down [with smaller doses of Jakafi]. She finally has great symptom control with this lower dose.” Despite all these ups and downs, Gina is happy with her treatment. Her symptoms are managed well, and she enjoys vacationing at the beach in her retirement.

A student asked, “I apologize if this is blunt: do you struggle with the cost of Jakafi? Is making Medicare pay for such a costly medication that just improves symptoms worth it?”

“The medication makes me feel much better. I was barely eating before I started Jakafi. The pain in my stomach [spleen] got better, it allowed me to sleep. My blood tests have improved. Jakafi had a crazy price tag when I first started taking in 2012. I am fortunate that my doctor enrolled me in a charity program that pays my share.” According to “U.S. Probe Sheds Light on Charities’ Role in Boosting Drug Sales,” (Wall Street Journal, June 2017), pharma companies are the primary donors to these “charities” because “every $1 million donated to charities can lead to up to $21 million in sales for drug companies.” In other words, patients are more likely to continue having their Medicare prescriptions filled if they don’t have to pay anything out of pocket.

Friday afternoon concluded with a practice clinical exam session. We interviewed a standardized patient with simulated heart failure (bibasilar crackles with S3 gallop). After the 30-minute encounter, we analyzed a (fake) electrocardiogram and chest x-ray, and then we spent 45 minutes writing a H&P (history and physical exam) note. Type-A Anita before the practice session: “I am so nervous. I do not know who we will have to write up. I don’t know if we should do vitals. I’m freaking out about having to read an EKG.”

Students throughout the day were checking news about the Las Vegas shooting. Pinterest Penelope updated our small group from BuzzFeed: “Isn’t that where Russian News propaganda is spread?” “Are you kidding, they have better live news updates than any other website.” “That’s because they don’t fact check anything.”

The weekly email from our director of academic counseling:

… in this Wellness Weekly section, inclusive language will be highlighted. The following details were taken directly from the University of Massachusetts–Amherst transgender terminology guide [from The Stonewall Center, “A Lesbian, Gay, Bisexual, Trans, Queer, Intersex, and Asexual (LGBTQIA+) Resource Center”]

• Hir: A non-gender specific pronoun used instead of “her” and “him.”
• Sie or Ze: A non-gender specific pronoun used instead of “she or “he.”
• Intersex: congenital variations in which development of chromosomal, gonadal, or anatomical sex is atypical (preferred term to “hermaphrodite”). About one in 1,500-2,000 children are born with an intersex variation.

She promises more information on the topic of transgender vocabulary in future editions, includes a recipes for Zucchini Parmesan Crisps (preheat oven to 450 and bake for 30 minutes), and advertises a yoga session taught by a full-fledged MD.

Statistics for the week… Study: 20 hours. Sleep: 8 hours/night; Fun: 1 nights. Example fun: Our social chair organized a 2:00 pm Saturday private wine tasting tour for $20 at a local winery attended by 15 students.